Institute of Physiology 1/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University, D-07740 Jena, Germany.
Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich-Schiller-University, D-07740 Jena, Germany.
Int J Mol Sci. 2024 Nov 6;25(22):11943. doi: 10.3390/ijms252211943.
Therapeutically, the Janus kinase (Jak) 1/Jak2 inhibitor baricitinib reduces the pathology of rheumatoid arthritis and may also reduce pain. Here, we investigated whether baricitinib directly affects joint nociceptors. We recorded action potentials from nociceptive C- and A∂-fibers of the normal and inflamed knee joint in anesthetized rats to monitor their responses to innocuous and noxious joint rotation. In isolated and cultured dorsal root ganglion (DRG) neurons, we examined Stat3 activation using Western blots and monitored excitability using patch-clamp recordings. Intra-articular injection of baricitinib did not alter C- and A∂-fiber responses to innocuous and noxious rotations of the normal knee but reduced C-fiber responses to these stimuli in inflamed joints. Baricitinib prevented the increase in C-fiber responses to joint rotation evoked by interleukin (IL)-6 plus soluble interleukin-6 receptor (sIL-6R) but not the increase evoked by TNF. In DRG neurons, baricitinib blocked Stat3 activation by hyper-IL-6, and baricitinib or the Stat3 inhibitor Sta21 prevented induction of hyperexcitability by IL-6 plus sIL-6R. Thus, neuronal Jaks are involved in the generation of C-fiber hyperexcitability induced by inflammation and IL-6. Pain reduction by baricitinib may result, at least in part, from direct effects on joint nociceptors.
治疗上，Janus 激酶（Jak）1/Jak2 抑制剂巴瑞替尼可减轻类风湿关节炎的病理变化，并且可能减轻疼痛。在这里，我们研究了巴瑞替尼是否直接影响关节伤害感受器。我们记录了麻醉大鼠正常和炎症膝关节伤害性 C 和 A∂-纤维的动作电位，以监测它们对无害和有害关节旋转的反应。在分离和培养的背根神经节（DRG）神经元中，我们使用 Western blot 检查 Stat3 的激活，并使用膜片钳记录监测兴奋性。关节内注射巴瑞替尼不会改变正常膝关节无害和有害旋转时 C 和 A∂-纤维的反应，但会减轻炎症关节中这些刺激引起的 C-纤维反应。巴瑞替尼可预防白细胞介素（IL）-6 加可溶性白细胞介素-6 受体（sIL-6R）引起的 C-纤维对关节旋转反应的增加，但不能预防由 TNF 引起的增加。在 DRG 神经元中，巴瑞替尼可阻断高 IL-6 引起的 Stat3 激活，巴瑞替尼或 Stat3 抑制剂 Sta21 可预防 IL-6 加 sIL-6R 诱导的过度兴奋。因此，神经元 Jak 参与了炎症和 IL-6 引起的 C-纤维过度兴奋的产生。巴瑞替尼减轻疼痛的作用可能至少部分来自对关节伤害感受器的直接作用。
